One of the most exciting technical developments in biology in recent years is the emergence of photochemical methods for controlling electrical activity with light. Our goal in this project is to develop a broadly applicable method for controlling other aspects of cellular function by generating tools for conferring light sensitivity on a broad range of cell surface receptors and ion channels. To meet this challenge we will use a modular approach, utilizing a single "Universal Photoswitch" as the key light-sensing component. The photoswitch contains at its core the small isomerizable azobenzene moiety, which shortens and lengthens in response to 380 and 500 nm light, respectively. We will use this photoswitch to indirectly regulate receptor and channel activity, through an "adapter peptide", which contains a "capture domain", which recognizes the short, but not the long configuration of the photoswitch, and a ligand domain, which contains a peptide activator or inhibitor of the targeted cell surface receptor or ion channel. The capture domain is kept constant among all adapter peptides, allowing control by a single Universal Photoswitch, but the nature of ligand domain is tailored to regulate a specific receptor. Several strategies will be used to translate light-dependent capture of the adapter peptide into receptor activation or inhibition. These include dimerizing the adapter peptide with a dimeric photoswitch to activate growth factor receptors, and delivering the adapter peptide, including the ligand, to a G-protein coupled receptor via an antibody-tethered photoswitch. Other strategies may be developed to activate different types of receptors and ion channels. We will test the effectiveness of the Universal Photoswitch approach on two example receptors: the TrkB receptor for brain-derived growth factor (BDNF), a member of the neurotrophin family of receptor tyrosine kinases, and the receptor for neuropeptide Y, which is a GPCR-type receptor. Generating a method for light-sensitive regulation of these receptors will allow examination of their roles in development and neural function in intact tissue with unprecedented precision, but more importantly, it will demonstrate the emergence of a powerful new technique for receptor regulation that can be applied to any cell surface protein for which a known peptide ligand exists. PUBLIC HEALTH RELEVANCE: Our goal is to develop a single photochemical switch that can be interfaced in a combinatorial manner with many types of cell surface receptors to enable precise temporal, spatial, and biochemical control over neuronal functions. The NIDA/NIMH/NINDS EUREKA applications were reviewed differently from more traditional NIH grant mechanisms. Specifically, the review process consisted of two phases. During the first (i.e., electronic) phase a selected panel of reviewers were given the following guidelines by which to assess the applications. They were asked to determine whether they: Strongly Agree, Moderately Agree, Neither Agree nor Disagree, Moderately Disagree, or Strongly Disagree with these descriptions. Their ratings and any additional comments are below. These initial ratings also provided the basis for the review panel to determine whether an application would be discussed during an in person meeting. Because of the very stringent review criteria and limited pool of funds set aside for this program, the review panel chose only to discuss applications that garnered the most enthusiasm. The Resume and Summary of the Discussion above summarizes opinions of the person meeting and forms the basis of the final score. Significance: This study addresses an important problem and the outcome of the proposed studies will drive the field. The potential impact of the proposed research is exceptional, in terms of the magnitude of the impact and the size of the community affected. Innovation: The project is highly original and exceptionally innovative and seriously challenges existing paradigms or clinical practice. The project addresses a major barrier to progress in the field or it develops or employs exceptionally novel concepts, approaches, methodologies, tools, or technologies. Approach: The logic of the approach is sufficiently compelling despite the lack of experimental detail. The conceptual (or clinical) framework, design, methods, and analyses are adequately developed, well integrated and reasoned, and are appropriate for the aims of the project. The applicant acknowledges potential problem areas and considers alternative tactics. The information in the timeline inspires confidence that the PI will be able to document progress in each year of the award and either complete the project or demonstrate conclusively that it cannot be completed, despite good-faith efforts, during the term of the award. The requested duration of the award is appropriate for the proposed research. Investigators: The PD/PI(s) and other key personnel are appropriately trained and well-suited to carry out this work. Past achievements of the PI(s) suggest that the investigator(s) is/are exceptionally innovative and likely to make paradigm-shifting, high-impact discoveries. If the PI does not have a history of doing exceptionally innovative, high-impact research, the logic of the experimental plan suggests that there is at least some likelihood of success. The project is high priority for the PI(s), as indicated by the person-months of effort that the PI(s) will devote to it. For applications designating multiple PDs/PIs, the leadership plan, including the designated roles and responsibilities, governance, and organizational structure, are consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs. Environment: The scientific environment(s), in which the work will be performed, contributes to the probability of success. The proposed studies benefit from unique features of the scientific environment, subject populations, or employ useful collaborative arrangements. There is evidence of institutional support.